Our joint laboratory discovered a direct link between CO2/HCO3/pH and intracellular signaling pathways when we demonstrated soluble adenylyl cyclase (sAC) is an evolutionarily conserved bicarbonate sensor. Over the past decade, we have collaborated with a variety of laboratories to prove that sAC serves as a CO2/HCO3/pH chemosensor in mammalian sperm, epididymis, airway epithelia, glia, and inside the mitochondrial matrix. In the most recent funding period, we discovered that the sAC gene is alternatively spliced and uses multiple promoters to generate a variety of isoforms. We now propose to (A) identify which isoforms are expressed in individual CO2/HCO3/pH sensing tissues;(B) which CO2/HCO3/pH sensing functions are abrogated in a knockout mouse which removes a subset of these sAC isoforms;and (C) determine whether the newly identified sAC isoforms are also CO2/HCO3/pH sensors. PUBLIC HEALTH RELEVANCE: CO2 and/or bicarbonate have been shown to modulate a number of physiological processes. We discovered the existence of a widely expressed signal transducing enzyme, sAC, which is directly modulated by bicarbonate ions. Because of the intimate relationship between bicarbonate, CO2 and pH, it is possible that some, if not all, of the CO2 dependent signaling processes are regulated by bicarbonate modulation of sAC and cAMP levels.